Therapeutic use of an enhanced form of CD4-Ig

增强型 CD4-Ig 的治疗用途

• 批准号: 10851165
• 负责人: Michael R. Farzan
• 金额: $ 20.01万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-04 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10851165
• 关键词: Antibodies; Antibody Response; Award; Collaborations; Dependovirus; Fc domain; HIV-1; Human; Infection; Instruction; Laboratories; Macaca mulatta; Mediating; Property; Residual state; Role; SIV; Serum; Technology; Therapeutic Uses; Transgenes; Viral; Viral reservoir; Virus Replication; adeno-associated viral vector; antiretroviral therapy; immune clearance; immunogenicity; improved; inhibitor; peptidomimetics; prevent; receptor; simian human immunodeficiency virus; tyrosine O-sulfate

eCD4-Ig is a potent and exceptionally broad fusion of the first two domains of CD4 to an antibody Fc domain and a short tyrosine-sulfated coreceptor-mimetic peptide. In rhesus macaques, adeno-associated virus (AAV)-expressed eCD4-Ig mediates consistent and very effective long-term protection against SHIV- AD8 and SIVmac239. eCD4-Ig also has properties that make it especially useful for establishing a functional cure in rhesus macaques and perhaps in humans. These include its potency, breadth, difficulty- of-escape, low immunogenicity when expressed by AAV, consistent expression by AAV, potent intrinsic ADCC activity, and collaboration with serum antibodies to mediate ADCC. These properties allow eCD4- Ig to circumvent two major problems associated with using AAV-expressed antibodies to establish functional cures, namely immune clearance and viral escape. In the forthcoming award period, we will improve the technologies allowing AAV-mediated delivery of eCD4-Ig by optimizing its expression as an AAV transgene, by eliminating residual antibody responses to AAV-delivered eCD4-Ig, and by assessing the role of the eCD4-Ig Fc domain in anti-eCD4-Ig antibody responses and in control an established SIVmac239 infection. These efforts will develop technologies that can be applied to the ongoing efforts by many laboratories to prevent new infections, to provide long- acting alternatives to combined antiretroviral therapies, and to reduce the scale of the viral reservoir. RELEVANCE (See instructions): eCD4-Ig is a potent and exceptionally broad HIV-1 and SIV entry inhibitor that, when delivered by an AAV vector, provides rhesus macaques robust long-term protection from new infections, and by itself suppresses viral replication in the absence of anti-retroviral therapies. Here we seek to optimize and better understand these properties of AAV-delivered eCD4-Ig.

ECD4-ig是CD4前两个结构域与抗体FC的有效且异常广泛的融合 结构域和短酪氨酸硫化的共感染者模拟肽。在恒河猕猴中，腺相关 病毒（AAV）表达的ECD4-Ig介导了一致且非常有效的长期保护，以防止SHIV- AD8和SIVMAC239。 ECD4-Ig还具有使其对建立一个特别有用的特性 在恒河猕猴的功能治疗，也许是在人类中。这些包括其效力，广度，难度 - 通过AAV表达，AAV，AAV，有效的固有表达时，eScape，低免疫原性 ADCC活动，并与血清抗体合作介导ADCC。这些特性允许ECD4- IG避免使用与使用AAV表达抗体建立的两个主要问题 功能治疗，即免疫清除和病毒逃生。 在即将举行的奖项期间，我们将改进允许AAV介导的交付的技术 通过消除残留的抗体反应，通过优化其作为AAV转基因的ECD4-Ig通过 通过评估ECD4-Ig FC结构域在抗ECD4-Ig抗体中的作用，使ECD4-ig分发了 反应并控制已建立的SIVMAC239感染。这些努力将开发技术 可以应用于许多实验室的持续努力，以防止新的感染，以提供长期的感染 合并抗逆转录病毒疗法的作用替代方法，并减少病毒储存剂的规模。 相关性（请参阅说明）： ECD4-Ig是一种有效且异常广泛的HIV-1和SIV进入抑制剂，当由 AAV矢量，提供恒河猕猴的坚固长期保护，免受新感染，本身 在没有抗返回病毒疗法的情况下抑制病毒复制。在这里，我们试图优化和 更好地了解AAV传递的ECD4-Ig的这些属性。